Rhabdoviruses are enveloped, bullet-shaped viruses (Figure 1). Each contains a helical nucleocapsid. The viruses in the family Rhabdoviridae known to infect mammals are divided into two genera: Lyssavirus (rabies virus, the rhabdovirus of greatest medical importance to humans), and Vesiculovirus [vesicular stomatitis virus (VSV), a virus of horses and cattle, and the best-studied virus in this family]. Other rhabdoviruses infect invertebrates, plants, or other vertebrates.

Fig1. Rabies virus. A. Schematic drawing. B. Electron micrograph.  

A. Epidemiology A wide variety of wildlife, such as raccoons, skunks, squirrels, foxes, and bats, provide reservoirs for the rabies virus (Figure 2B). In developing countries, domestic dogs and cats also constitute important reservoirs for rabies. Cases of human rabies are rare in the United States. However, in developing areas, such as rural Africa and Asia, rabies causes approximately 55,000 deaths a year. Humans are usually infected by the bite of an animal, but, in some cases, infection is via inhalation (for example, of droppings from infected bats). Sequence analysis of the viral RNA has shown that most human cases in the United States are from a bat strain of rabies virus.

Fig2. A. Schematic representation of pathogenesis of rabies infection. B. Wildlife rabies in the United States.

B. Viral replication

The genomic negative-strand RNA is nonsegmented. The virion contains five proteins, one of which, the G (for “glyco-“) protein, is an envelope protein composed of viral spikes (see Figure 1). The rabies virion attaches via its glycoprotein spikes to cell-surface receptors. It enters the cell via receptor-mediated endocytosis, following which the viral envelope fuses with the endocytotic vesicle’s membrane, releasing the viral nucleocapsid into the cytosol, where replication occurs. Five different mRNAs are transcribed from the genomic RNA template by the virion’s RNA-dependent RNA polymerase (transcriptase function), each of which encodes one viral protein. The polymerase that produces the mRNA also synthesizes positive-strand copies of the viral RNA template (replicase function), from which new negative-strand RNA genomic molecules can be transcribed. Viral structural proteins plus the negative-strand viral RNA form new helical nucleocapsids, which move to the cell surface. There, each nucleocapsid acquires its envelope by budding through a region of virus-modified plasma membrane.

C. Pathology

Following inoculation, the virus may replicate locally but then travels via retrograde transport within peripheral neurons to the brain, where it replicates primarily in the gray matter (Figure 2A). From the brain, the rabies virus can travel along autonomic nerves, leading to infection of the lungs, kidney, adrenal medulla, and salivary glands. [Note: Contamination of saliva potentially leads to further transmission of the disease (for example, through a bite from an infected animal).] The extremely variable incubation period depends on the host’s resistance, amount of virus transferred, and distance of the site of initial infection from the central nervous system (CNS). Incubation generally lasts 1 to 8 weeks but may range up to several months or, in unusual cases, as long as several years following exposure. Clinical illness may begin with an abnormal sensation at the site of the bite, then progress to a fatal encephalitis, with neuronal degeneration of the brain and spinal cord. Symptoms include hallucinations; seizures; weakness; mental dysfunction; paralysis; coma; and, finally, death. Many, but not all, patients show the classic rabid sign of hydrophobia. In this case, “hydrophobia” refers to the infected individual’s painful inability to swallow liquids (due to pharyngeal spasms), leading to avoidance. Once symptoms begin, death is almost always inevitable.

D. Laboratory identification

 Clinically, diagnosis rests on a history of exposure and signs and symptoms characteristic of rabies. However, a reliable history of exposure is often not obtainable, and the clinical presentation, especially in the initial stages, may not be characteristic. Therefore, a clinical diagnosis may be difficult. Postmortem, in approximately 80 percent of cases, characteristic eosinophilic cytoplasmic inclusions (Negri bodies) may be identified in certain regions of the brain such as the hippocampus. These cytoplasmic inclusion bodies are virus production foci and diagnostic of rabies (Figure 3). Prior to death, the diagnosis can be made by identification of viral antigens in biosies of skin from the back of the neck or from corneal cells or by demonstration of the viral nucleic acid by reverse transcription polymerase chain reaction (RT-PCR) in infected saliva.

Fig3. An oval Negri body in a brain cell from a human rabies case.

E. Treatment and prevention

Once an individual has clinical symptoms of rabies, there is no effective treatment. However, a killed rabies virus vaccine is available for prophylaxis. In the United States, two vaccine formulations are approved by the Food and Drug Administration. Both contain inactivated virus grown in cultured cells (chick embryo cells or human diploid cells). Preexposure prophylaxis is indicated for individuals at high risk because of the work they do (for example, for veterinarians). Postexposure prophylaxis refers to treatment instituted after an animal bite or exposure to an animal (or human) suspected of being rabid, and consists of thorough cleaning of the wound, passive immunization with antirabies immunoglobulin, and active immunization with the rabies vaccine (HDCV, the human diploid cell vaccine). Prevention of initial exposure is, however, clearly the most important mechanism for controlling human rabies.

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